Method for the preparation of citalopram

ABSTRACT

The invention provides a new and improved method for the preparation of 5-cyano-phtalid, which is a key intermediate in the preparation of the antidepressant compound citalopram.

[0001] This application is a continuation of International applicationno. PCT/DK99/00740, filed Dec. 30, 1999. The disclosure of the priorapplication is hereby incorporated by reference.

[0002] The present invention relates to a method for the preparation ofkey intermediates in the process for the preparation of the well knownantidepressant drug citalopram,1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile.

BACKGROUND OF THE INVENTION

[0003] Citalopram is a well known antidepressant drug that has now beenon the market for some years and has the following structure:

[0004] It is a selective, centrally acting serotonin(5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly havingantidepressant activities. The antidepressant activity of the compoundhas been reported in several publications, eg. J. Hyttel, ProgNeuro-Psychopharmacol. & Biol. Psychiat., 1982, 6, 277-295 and A.Gravem, Acta Psychiatr. Scand., 1987, 75, 478-486. The compound hasfurther been disclosed to show effects in the treatment of dementia andcerebrovascular disorders, EP-A 474580.

[0005] Citalopram can be prepared by several disclosed methods. A methodand an intermediate for the preparation of citalopram were described inU.S. Pat. No 4,650,884. Commercially useful processes are disclosed inInternational patent application Nos. WO 98019511, WO 98019512 and WO98019513.

[0006] With respect to the above methods for the preparation ofcitalopram, the process comprising exchange of the 5-bromo group withcyano proved not to be very convenient in commercial scale, since theyield was rather low, the product was impure and, in particular, sinceit was difficult to separate the resulting citalopram from thecorresponding 5-bromo compound.

[0007] It has now been found that in a new process for the preparationof citalopram, this key intermediate may be obtained in a high yield asa very pure product by a new catalytic process in which a halogen or agroup of the general formula CF₃—(CF₂)_(n)—SO₂— wherein n is anysuitable whole number between 0 and 4, situated in the 5-position of a3-H-isobenzofuran-1-one, is exchanged with a cyanide group. By obtainingthe correct cyanide substitution at an early stage of the citalopramsynthesis, the extensive work up of the old cyanide exchange processesof the previous described processes is avoided. The intermediates of thepresently described process are easily purified and obtained in veryhigh yields. The key intermediate is then subjected to two successiveGrignard reactions, i.e. with 4-fluorophenyl magnesium halogenide andN.N-dimethylaminopropyl magnesium halogenide, respectively, wherebycitalopram is obtained.

[0008] The preparation of the key intermediate of the invention isdescribed earlier in J.Chem. Soc., 1931, 867 and by Tiroflet, J. inBull. Soc. Sci. Betagne, 26, 35, 1951. The process for preparation ofthe compound is a three step synthesis starting from 5-nitro-phtalimidewith low yields, especially in the last step of the synthesis.

SUMMARY OF THE INVENTION

[0009] Accordingly, the present invention relates to a novel method forthe preparation of an intermediate in the preparation of citalopramcomprising reacting a compound of Formula IV

[0010] wherein R′ is Cl, Br, I or a group of the formulaCF₃—(CF₂)_(n)—SO₂—, wherein n is 0-4, with a cyanide source in thepresence or absence of a catalyst, whereby 5-cyano-isobenzofuran-1-oneis obtained. This intermediate product can be further reacted tocitalopram as described above.

[0011] The reaction of IV to 5-cyanophtalide may be carried out in moreconvenient solvents, at a low temperature and at a minimal excess ofCN⁻. The process has environmental advantages in that it only uses smallamounts of heavy metals.

[0012] The cyano sources may conveniently be selected from a groupconsisting of cyanide sources such as (R″₄N)CN wherein each R″represents C₁₋₈-alkyl optionally two R″ together with the nitrogen forma ring structure; NaCN, KCN, Zn(CN)₂ or Cu(CN).

[0013] The reaction of the present invention is performed in thepresence or absence of a catalyst. The catalysts are i.e. Ni (0), Pd(0)or Pd(II) catalysts as described by Sakakibara et. al. in Bull. Chem.Soc. Jpn., 61, 1985-1990, (1988). Preferred catalysts are Ni(PPh₃)₃ orPd(PPh₃)₄, or Pd(PPh)₂Cl₂.

[0014] In a particularly preferred embodiment, a Nickel(0) complex isprepared in situ before the cyanide exchange reaction by reduction of aNickel(II) precursor such as NiCl₂ or NiBr₂ by a metal, such as zinc,magnesium or mangan in the presence of excess of complex ligands,preferably triphenylphosphin.

[0015] The Pd or Ni-catalyst is conveniently used in an amount of0.5-10, preferably 2-6, most preferably about 4-5 mol %.

[0016] Cu⁺ and Zn²⁺ may be added to the reaction mixture insubstoichiometric amounts and may function as recycleable cyanidesources, which receives the cyanide from other cyanide sources such asNaCN or KCN. Substoichiometric amounts of Cu⁺ and Zn²⁺, respectively,means 1-20%, preferably 5-10%.

[0017] The reactions may be performed in any convenient solvent asdescribed in Sakakibara et. al. in Bull. Chem. Soc. Jpn., 61, 1985-1990,(1988). Preferred solvents are acetonitrile, ethylacetate, THF, DMF orNMP;

[0018] In one aspect of the invention, a compound of Formula IV whereinR is Cl is reacted with NaCN in the presence of a Ni(PPh₃)₃ which ispreferably prepared in situ as described above.

[0019] In another aspect of the invention, a compound of formula IV,wherein R is Br or I, is reacted with KCN, NaCN, CuCN or Zn(CN)₂ in thepresence of Pd(PPh₃)₄. In a particular aspect of the invention,substoichiometric amounts of Cu(CN) and Zn(CN)₂ are added as recycleablecyanide sources.

[0020] In another aspect of same invention, the Cu(CN) is the cyanidesource and without catalyst. In a preferred embodiment of thisinvention, the reaction is performed at elevated temperature.

[0021] In a particular aspect of this invention, the reaction isperformed as a neat reaction i.e. without added solvent.

[0022] In another aspect of the invention, the reaction is performed inan ionic liquid of the general formula R₄N⁺, X⁻, wherein R arealkyl-groups or two of the R groups together form an ring and X⁻ is thecounterion. In one embodiment of the invention, R₄N⁺X⁻ represents

[0023] In another particular aspect of this invention, the reaction isconducted with apolar solvents such as benzene, xylene or mesitylene andunder the influence of microwaves by using i.e. Synthewave 1000™ byProlabo. In a particular aspect of this invention, the reaction isperformed without added solvent.

[0024] The temperature ranges are dependent upon the reaction type. Ifno catalyst is present preferred temperatures are in the range of100-200° C. However, when the reaction is conducted under the influenceof microwaves the temperature in the reaction mixture may raise to above300° C. More preferred temperature ranges are between 120-170° C. Themost preferred range is 130-150° C.

[0025] If catalyst is present, the preferred temperature range isbetween 0 and 100° C. More preferred are temperature ranges of 40-90° C.Most preferred temperature ranges are between 60-90° C.

[0026] Other reaction conditions, solvents, etc. are conventionalconditions for such reactions and may easily be determined by a personskilled in the art.

EXAMPLES

[0027] The invention is further illustrated by the following examples.

Experimental Example 1

[0028]

[0029] A mixture of Zn(CN)₂ (2.4 g, 0.02 mol) and5-bromo-3H-isobenzofuran-1-one (4.2 g, 0.02 mol) in DMF (80 mL) werestirred at room temperature under an atmosphere of argon for 30 minutes.Then dissolved oxygen was removed by bubbling argon through the reactionmixture for 10 minutes before the addition oftetrakis(triphenylphosphine)palladium (0) (1.2 g, 0.00096 mol,). Thenthe reaction was heated at 75° C. for 3 hrs, and then the solvent wasremoved under reduce pressure and the residue poured into water (150mL). Filtration and followed by drying in vacuo give the crude5-cyano-3H-isobenzofuran-1-one (2.8 g) (HPLC 95%). An analytical samplewas obtained by recrystalisation from acetic acid.

Example 2

[0030] A mixture of Zn(CN)₂ (0.3 g, 0.00256 mol), NaCN (1 g, 0,02 mol)and 5-bromo-3H-isobenzofuran-1-one (4.2 g, 0.02 mol) in DMF (80 mL) werestirred at room temperature under an atmosphere of argon for 30 minutes.Then dissolved oxygen was removed by bubbling argon through the reactionmixture for 10 minutes before the addition oftetrakis(triphenylphosphine)palladium (0) (1.2 g, 0.00096 mol). Then thereaction was heated at 75° C. for 3 hrs, and then the solvent wasremoved under reduce pressure and the residue poured into water (150mL). Filtration and followed by drying in vacuo give the crude5-cyano-3H-isobenzofuran-1-one (2.7 g) (HPLC 94%). An analytical samplewas obtained by recrystalisation from acetic acid.

Example 3

[0031] A mixture of 5-bromo-3H-isobenzofuran-1-one (4.2 g, 0.02 mol) andCu(CN)₂ (2.3 g, 0.02 mol) in NMP (60 mL) were stirred at 140° C. for3hrs. Then solvent was removed by distilation under reduced pressure andthe residue was refluxed in water (150 mL) for 10 minutes and allowed tocool to room temperature. Filtration and followed by drying in vacuogive the crude 5-cyano-3H-isobenzofuran-1-one (2.1 g) (HPLC 97%). Ananalytical sample was obtained by recrystalisation from acetic acid.

Example 4

[0032] A mixture of Zn(CN)₂ (2.4 g, 0.02 mol) and5-iodo-3H-isobenzofuran-1-one (5.24 g, 0.02 mol) in DMF (80 mL) werestirred at room temperature under an atmosphere of argon for 30 minutes.Then dissolved oxygen was removed by bubbling argon through the reactionmixture for 10 minutes before the addition oftetrakis(triphenylphosphine)palladium (0) (1.2 g, 0.00096 mol). Then thereaction was heated at 75° C. for 3 hrs, and then the solvent wasremoved under reduce pressure and the residue poured into water (150mL). Filtration and followed by drying in vacuo give the crude5-cyano-3H-isobenzofuran-1-one (2.4 g) (HPLC 93%). An analytical samplewas obtained by recrystalisation from acetic acid.

Example 5

[0033] Under a nitrogen atmosphere, a mixture of NiCl₂ (0.2 g, 0.0015mol) and triphenylphosphine (1.6 g, 0.0061 mol) in acetonitrile (80ml)was heated at reflux for 45 minutes. After cooling to roomtemperature, zinic powder was added (0.39 g, 0.006 mol) at stirred for15 minutes before a solution of 5-chloro-3H-isobenzofuran-1-one (3.4 g,0.02 mol) in THF (40 mL) was added. After stirring for a further 10minutes, NaCN (1.1 g, 0.021 mol) was added and the reaction heated at70° C. for 3 hrs, cooled, diluted with acetonitrile (50 mL), and thenfiltered through celite. The filtrate was concentrated under reducedpressure and the residue was refluxed in water (150 mL) for 10 minutesand allowed to cool to room temperature. Filtration and followed bydrying in vacuo give the crude 5-cyano-3H-isobenzofuran-1-one (2.5 g).An analytical sample was obtained by recrystalisation from acetic acid.

1. A method for the preparation of a compound of the formula

comprising reacting an isobenzofuran-1-one of the formula

wherein R′ is a halogen or CF₃—(CF₂)_(n)—SO₂—, wherein n is 0-7, with acyanide source optionally in the presence of a catalyst.
 2. The processof claim 1 wherein R′ is Cl, Br or I.
 3. The process of claim 1 whereinR′ is CF₃—(CF₂)_(n)—SO₂—, wherein n is 0, 1,2,3 or
 4. 4. The process ofclaim 1, wherein the cyanide source is selected from (R″₄N)CN whereineach R″ is C₁₋₈-alkyl, optionally two R″ together with the nitrogen forma ring structure; KCN, NaCN, Zn(CN)₂ or CuCN or combinations thereof. 5.The process of claim 1, wherein Zn²⁺ or Cu⁺ are added insubstoichiometric amounts in combination with another cyanide source. 6.The process of claim 1, wherein the catalyst is selected from Ni(PPh₃)₃,Pd(PPh₃)₄, Pd(dba)₃ or Pd(PPh)₂Cl₂.
 7. The process of claim 1, wherein a5-chloro-isobenzofuran-1-one is subjected to NaCN in the presence ofNi-catalyst.
 8. The process of claim 7 wherein the Ni-catalyst isNi(PPh₃)₃ prepared in situ by subjecting NiCl₂ to a reducing agent, inthe presence of PPh₃.
 9. The process of claim 8 wherein the reducingagent is Zn.
 10. The process of claim 1, wherein a 5-bromo- or5-iodo-isobenzofuran-1-one is subjected to KCN, NaCN, Zn(CN)₂, or CuCNor combinations thereof in the presence of Pd(PPh₃)₄.
 11. The processaccording to claim 1, 2 and 4 wherein a 5-bromo- or5-iodo-isobenzofuran-1-one is subjected to KCN, NaCN, Zn(CN)₂, or CuCNor combinations thereof and the process is performed without catalysts.12. The process of claim 10 wherein the reaction is performed in anionic liquid of the general formula R₄N⁺X⁻ wherein each R representsC₁₋₈-alkyl optionally two R″ together with the nitrogen form a ring. 13.The process of claim 10 wherein the reaction is performed under theinfluence of microwaves in an apolar solvent.
 14. The process accordingto claim 10 or claim 12 wherein the reaction is performed as a neatreaction.